Skip to main content

Advertisement

SpringerLink
Log in

Utility of Göttingen minipigs for Prediction of Human Pharmacokinetic Profiles After Dermal Drug Application

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

Abstract

Purpose

Although Göttingen minipigs have been widely used for the evaluation of skin absorption, the correlation of minipig skin permeability with human skin absorption remains unclear. This study was designed to investigate the prediction of human plasma concentrations after dermal application of drug products using skin permeability data obtained from minipigs.

Methods

First, in vitro skin permeabilities of seven marketed transdermal drug products were evaluated in minipigs, and compared with in vitro human skin permeability data. Next, plasma concentration-time profiles in humans after dermal applications were simulated using the in vitro minipig skin permeability data. Finally, the in vitro-in vivo correlation of minipig skin permeability was assessed.

Results

The in vitro skin permeabilities in minipigs were correlated strongly with in vitro human skin permeability data for the same drug products, indicating the utility of minipig skin as an alternative to human skin for in vitro studies. The steady-state plasma concentration or the maximum concentration of drugs was within 2-fold of the clinical data. Bioavailability was approximately 3-fold lower than in vitro permeated fraction.

Conclusions

Predictions using in vitro skin permeability data in Göttingen minipig skin can reproduce the human pharmacokinetic profile, although the prediction of in vivo skin absorption underestimates human absorption.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

AUC:

Area under the concentration-time curve

BA:

Bioavailability

HPLC:

High-performance liquid chromatography

LC/MS/MS:

Liquid chromatography/tandem mass spectrometer

MRT:

Mean residence time

REFERENCES

  1. Adler G, Mueller B, Articus K. The transdermal formulation of rivastigmine improves caregiver burden and treatment adherence of patients with Alzheimer's disease under daily practice conditions. Int J Clin Pract. 2014;68(4):465–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Yamamoto S, Karashima M, Arai Y, Tohyama K, Amano N. Prediction of human pharmacokinetic profile after transdermal application using excised human skin. J Pharm Sci. 2017;106(9):2787–2794.

  3. Qvist MH, Hoeck U, Kreilgaard B, Madsen F, Frokjaer S. Evaluation of Gottingen minipig skin for transdermal in vitro permeation studies. Eur J Pharm Sci. 2000;11(1):59–68.

    Article  CAS  PubMed  Google Scholar 

  4. Schmook FP, Meingassner JG, Billich A. Comparison of human skin or epidermis models with human and animal skin in in-vitro percutaneous absorption. Int J Pharm. 2001;215(1–2):51–6.

    Article  CAS  PubMed  Google Scholar 

  5. Priborsky J, Muhlbachova E. Evaluation of in-vitro percutaneous absorption across human skin and in animal models. J Pharm Pharmacol. 1990;42(7):468–72.

    Article  CAS  PubMed  Google Scholar 

  6. Stricker-Krongrad A, Shoemake CR, Liu J, Brocksmith D, Bouchard G. The importance of minipigs in dermal safety assessment: an overview. Cutan Ocul Toxicol. 2017:36(2):105–113.

  7. Dick IP, Scott RC. Pig ear skin as an in-vitro model for human skin permeability. J Pharm Pharmacol. 1992;44(8):640–5.

    Article  CAS  PubMed  Google Scholar 

  8. Sato K, Sugibayashi K, Morimoto Y. Species differences in percutaneous absorption of nicorandil. J Pharm Sci. 1991;80(2):104–7.

    Article  CAS  PubMed  Google Scholar 

  9. Singh S, Zhao K, Singh J. In vitro permeability and binding of hydrocarbons in pig ear and human abdominal skin. Drug Chem Toxicol. 2002;25(1):83–92.

    Article  CAS  PubMed  Google Scholar 

  10. Barbero AM, Frasch HF. Pig and guinea pig skin as surrogates for human in vitro penetration studies: a quantitative review. Toxicol in Vitro. 2009;23(1):1–13.

    Article  CAS  PubMed  Google Scholar 

  11. Tse FL, Laplanche R. Absorption, metabolism, and disposition of [14C]SDZ ENA 713, an acetylcholinesterase inhibitor, in minipigs following oral, intravenous, and dermal administration. Pharm Res. 1998;15(10):1614–20.

    Article  CAS  PubMed  Google Scholar 

  12. Gschwind HP, Waldmeier F, Zollinger M, Schweitzer A, Grassberger M. Pimecrolimus: skin disposition after topical administration in minipigs in vivo and in human skin in vitro. Eur J Pharm Sci. 2008;33(1):9–19.

    Article  CAS  PubMed  Google Scholar 

  13. Pershing LK, Huether S, Conklin RL, Krueger GG. Cutaneous blood flow and percutaneous absorption: a quantitative analysis using a laser Doppler velocimeter and a blood flow meter. J Investig Dermatol. 1989;92(3):355–9.

    Article  CAS  PubMed  Google Scholar 

  14. Clarys P, Alewaeters K, Jadoul A, Barel A, Manadas RO, Preat V. In vitro percutaneous penetration through hairless rat skin: influence of temperature, vehicle and penetration enhancers. Eur J Pharm Biopharm. 1998;46(3):279–83.

    Article  CAS  PubMed  Google Scholar 

  15. Auclair F, Besnard M, Dupont C, Wepierre J. Importance of blood flow to the local distribution of drugs after percutaneous absorption in the bipediculated dorsal flap of the hairless rat. Skin Pharmacol. 1991;4(1):1–8.

    Article  CAS  PubMed  Google Scholar 

  16. Hatanaka T, Kamon T, Morigaki S, Katayama K, Koizumi T. Ion pair skin transport of a zwitterionic drug, cephalexin. J Control Release. 2000;66(1):63–71.

    Article  CAS  PubMed  Google Scholar 

  17. Manevski N, Swart P, Balavenkatraman KK, Bertschi B, Camenisch G, Kretz O, et al. Phase II metabolism in human skin: skin explants show full coverage for glucuronidation, sulfation, N-acetylation, catechol methylation, and glutathione conjugation. Drug Metab Dispos. 2015;43(1):126–39.

    Article  CAS  PubMed  Google Scholar 

  18. Jung EC, Maibach HI. Animal models for percutaneous absorption. J Appl Toxicol. 2015;35(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  19. Bollen P, Ellegaard L. The Gottingen minipig in pharmacology and toxicology. Pharmacol Toxicol. 1997;80(Suppl 2):3–4.

    Article  CAS  PubMed  Google Scholar 

  20. Simianer H, Kohn F. Genetic management of the Gottingen Minipig population. J Pharmacol Toxicol Methods. 2010;62(3):221–6.

    Article  CAS  PubMed  Google Scholar 

  21. Benowitz NL, Jacob P 3rd, Denaro C, Jenkins R. Stable isotope studies of nicotine kinetics and bioavailability. Clin Pharmacol Ther. 1991;49(3):270–7.

    Article  CAS  PubMed  Google Scholar 

  22. Hossain M, Jhee SS, Shiovitz T, McDonald C, Sedek G, Pommier F, et al. Estimation of the absolute bioavailability of rivastigmine in patients with mild to moderate dementia of the Alzheimer's type. Clin Pharmacokinet. 2002;41(3):225–34.

    Article  CAS  PubMed  Google Scholar 

  23. Willis JV, Kendall MJ, Flinn RM, Thornhill DP, Welling PG. The pharmacokinetics of diclofenac sodium following intravenous and oral administration. Eur J Clin Pharmacol. 1979;16(6):405–10.

    Article  CAS  PubMed  Google Scholar 

  24. Olkkola KT, Isohanni MH, Hamunen K, Neuvonen PJ. The effect of erythromycin and fluvoxamine on the pharmacokinetics of intravenous lidocaine. Anesth Analg. 2005;100(5):1352–6. table of contents

    Article  CAS  PubMed  Google Scholar 

  25. Leopold G, Pabst J, Ungethum W, Buhring KU. Basic pharmacokinetics of bisoprolol, a new highly beta 1-selective adrenoceptor antagonist. J Clin Pharmacol. 1986;26(8):616–21.

    Article  CAS  PubMed  Google Scholar 

  26. Drugs Interview Form, Bisono® Tape 8mg. Pharmaceuticals and Medical Devices Agency http://www.info.pmda.go.jp/.

  27. Urae A. Comparative bioavailability study of Ba37I42 (Nicotine TTS) after a single application to different skin sites in Japanese smokers. J Clin Therap Med. 1994;10(3):53–62.

    Google Scholar 

  28. Drugs Interview Form, RIVASTACH® Path 18mg. Pharmaceuticals and Medical Devices Agency. http://www.info.pmda.go.jp/.

  29. Yokota H. Safety and Pharmacokinetic Study of L-740. Clin Rep. 1992;26(12):4711–22.

    Google Scholar 

  30. Drugs Interview Form, EMLA® CREAM. Pharmaceuticals and Medical Devices Agency. http://www.info.pmda.go.jp/.

  31. Drugs Interview Form, Voltaren® Tape 30 mg. Pharmaceuticals and Medical Devices Agency. http://www.info.pmda.go.jp/.

  32. Radermacher J, Jentsch D, Scholl MA, Lustinetz T, Frolich JC. Diclofenac concentrations in synovial fluid and plasma after cutaneous application in inflammatory and degenerative joint disease. Br J Clin Pharmacol. 1991;31(5):537–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Takeuchi H. Prediction of blood concentration of nicotine or lidocaine after application of their dermal tapes in human from the in vitro permeation through Yucatan micropig skin. Arch Pract Pharm. 2012;72(4):251–61.

    CAS  Google Scholar 

  34. Meyer W, Neurand K. Comparison of skin pH in domesticated and laboratory mammals. Arch Dermatol Res. 1991;283(1):16–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Drug Metabolism and Pharmacokinetics Research Laboratories, Research, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, Japan

    Syunsuke Yamamoto, Noriyasu Sano, Chiharu Fukushi, Kimio Tohyama, Hideki Hirabayashi & Nobuyuki Amano

  2. Analytical Development, Pharmaceutical Sciences, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa, Japan

    Masatoshi Karashima & Yuta Arai

Authors
  1. Syunsuke Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masatoshi Karashima
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Noriyasu Sano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chiharu Fukushi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kimio Tohyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuta Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hideki Hirabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Nobuyuki Amano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Syunsuke Yamamoto.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamamoto, S., Karashima, M., Sano, N. et al. Utility of Göttingen minipigs for Prediction of Human Pharmacokinetic Profiles After Dermal Drug Application. Pharm Res 34, 2415–2424 (2017). https://doi.org/10.1007/s11095-017-2247-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-017-2247-7

KEY WORDS

Search

Navigation